This application for a K24 Midcareer Investigator Award in Patient-Oriented Research is intended to promote mentoring activities and career development focused on the immunology of aging. Notably, no other currently funded K24 at the NIA is devoted to translational immunology. The PI, Dr. Shaw, is Associate Professor of Medicine at the Yale School of Medicine; he is trained in Internal Medicine and Infectious Disease, and in addition has a Ph.D. in Genetics and is a trained immunologist. Dr. Shaw is recognized as an authority on the aging of the human immune system; his lab has a special interest in aging of the innate immune system, and has carried out the largest and most comprehensive studies to date of the consequences of aging on human Toll-like Receptor (TLR) function. These studies defined features of immunosenescence in the innate immune system, and also demonstrated the linkage between TLR function and adaptive immune responses such as antibody response to influenza vaccine. Although Dr. Shaw has mentored several young investigators who remain in academic research positions, at present his mentoring activities must compete with administrative, clinical and research commitments. In this regard, he is at an ideal point in his career to expand his mentoring activities through the K24 mechanism. Dr. Shaw has recently begun two newly funded projects in patient- oriented research-in the first, he serves as Project Leader for an NIAID contract focusing on understanding age-associated alterations in innate immune pattern recognition receptor function. In the second, he is the PI of an R01 within a U19 Center Grant that is part of the NIH Human Immunophenotyping Consortium. This project will elucidate immunologic and gene expression signatures of influenza vaccine response, and will determine how aging and frailty affect these signatures. These two initiatives form the platform for development of a mentoring and career development plan directed to developing new investigators studying the immunology of aging. In addition, two additional projects would be directly supported by this application: the first, a pilot study of innate immune function in young and older individuals with HIV infection. The second exploratory project leverages an ongoing NIA-sponsored clinical trial at Yale of a multicomponent intervention of upright feeding position and enhanced oral care on nursing home pneumonia prevention. We will evaluate the relationship between innate immune function and results of an ongoing substudy on alterations in oral microbiome composition with enhanced oral care. This research platform will be supported by career development activities that include tutorials in clinical geriatrics, computational biology, and gerontologic biostatistic. Taken together, this program will further enhance the PI's role as a mentor to the next generation of investigators who will advance our understanding of human immunology in the context of aging.